The George M. O'Brien Urology Research Center at the University of Pennsylvania is an inter-institutional, multidisciplinary program that focuses its research on the molecular mechanisms underlying smooth muscle dysfunction in partial urinary bladder outlet obstruction (PBOO). The Center has three key elements: 1) the laboratories of five principal investigators and Co-PIs who bring expertise in molecular biology, cellular biology, biochemistry, physiology, pharmacology, and pathology; 2) an administrative core (Core A) to provide administrative oversight, quality control of projects, coordination of the research and interactions in the Urology Center; and 3) a bladder tissue core (Core B) to serve as a resource for smooth muscle tissue from animal models (rabbits and mice) for PBOO as well as human bladder tissue from surgical specimens. The projects are, 1: Extracellular Matrix Changes in Response to Obstruction (Macarak), 2: Effect of Extracellular Matrix and Stretch on the Expression of Smooth Muscle Phenotype during Detrusor Smooth Muscle Remodeling (DiSanto), 3: Cellular and Molecular Basis of Detrusor Contractility and Bladder Dysfunction in obstruction-induced detrusor remodeling (Chacko), and 4 A&B: Mechanism for the regulation of cross-bridge cycling and force generation and maintenance in bladder remodeling following outlet obstruction (Moreland & Barsotti). In addition, we have two Cores, a Bladder Tissue Core (Zderic), and an Administrative Core (Chacko & Wein), and two Pilot & Feasibility Projects. These are 1) Dimunition of Detrusor Hypertrophy in Outlet Obstruction by Inhibition of Calcineurine Pathway with Cyclosporin (Zderic) and (2) Phospholipase Activation During Bladder Obstruction (LaBelle). The new proposal will determine which signal transduction pathways lead to Ca2+-sensitization, actin-myosin interaction, crossbridge cycling, and how they are altered in the remodeling detrusors. Furthermore, it will help to establish which changes are reversible upon removal of the obstruction, and which molecular events are not reversible in the bladders that continue to be dysfunctional even after reversal of the obstruction. Data from these studies would help elucidate the cellular/molecular basis for the alteration of detrusor contractility following PBOO, to identify molecular markers that can be used to determine which obstructed bladder is remodeled beyond a point that contractile dysfunction is irreversible, and to target molecular steps for developing therapy.